Chronic and excessive alcohol consumption is the third leading cause of preventable death in the US with two million Americans afflicted with alcoholic liver disease. Like many diseases, the etiology of alcoholic liver disease is complex and a product of multiple gene-environment-metabolic interactions and disturbances. For example, alcohol-dependent dysregulation of multiple signaling pathways leads to increased lipogenesis, decreased fatty acid oxidation and excess lipid accumulation in liver. Chronic alcohol consumption is also known to alter circadian behavior;these behaviors are directly regulated by circadian clocks, which are present in virtually all mammalian cells including those of the central (suprachiasmatic nucleus, SCN) and peripheral (liver) tissues. Both environmental and genetic disruption of clock-mediated pathways results in desynchronization of an organism with its environment, as well as desynchrony between organs/tissues, resulting in cellular dysfunction and pathology. Whether inter-organ desynchrony, in turn, contributes to alcoholic tissue injury is not known. Accordingly, this proposal has the goal of investigating the molecular pathways and targets through which chronic ethanol disrupts circadian clocks leading to hepatic steatosis and injury. This proposal builds on new findings that the cardiomyocyte circadian clock directly regulates myocardial triglyceride turnover, channeling fatty acids into triglyceride synthesis at the end of the active period in mice. Consistent with the extra-cardiac significance of these observations, feeding mice a high fat diet specifically at the end of the active period results in adiposity, hyperinsulinemia, and hypertriglyceridemia, which are independent of total daily caloric quantity. As these same metabolic derangements can result from chronic ethanol consumption and are linked to steatosis, we propose that the hepatocyte circadian clock regulates liver triglyceride metabolism and that the time-of-day at which ethanol is consumed may markedly influence the development of hepatic steatosis. Thus, our long-term goal is to investigate whether chronic ethanol-induced steatosis and liver dysfunction are due, in part, to circadian desynchrony between the central (SCN) clock and the liver (hepatocyte) clock. Two initial questions that require interrogation include: (1) does chronic ethanol consumption cause circadian desynchrony between the SCN and liver, and (2) does the hepatocyte circadian clock directly influence ethanol-induced alterations in liver triglyceride metabolism and steatosis? Underscoring the high risk and high impact nature of this inter-disciplinary R21 application, is the fact that these studies have the goal to address a previously unchallenged hypothesis that circadian desynchrony between the brain and liver significantly contributes towards alcoholic liver injury. To date, studies designed to determine the impact of chronic ethanol consumption on liver function (and pathology) have ignored the temporal nature of ethanol consumption in humans. Completion of the proposed aims will likely highlight the circadian clock as a novel molecular mechanism influencing ethanol-induced liver pathology. PUBLIC HEALTH RELEVANCE: Alcohol abuse is estimated to be the third leading cause of preventable death in the United States. New studies report an increasing prevalence and severity of liver diseases from all causes in the United States. It has also become clear in recent years that chronic alcohol consumption disrupts many sub-cellular metabolic pathways in liver cells and that these disrupted processes contribute to the development of disease. The studies in this application are important as they will attempt to answer the question: What are the roles of other metabolic factors in worsening liver disease in the chronic alcohol consumer? Specifically, this research project will study the role of cellular circadian rhythms or clocks in alcoholic liver disease. Research in this area will help medical professionals better understand the causes of liver disease and lead to the discovery of new treatments for patients suffering from liver diseases associated with diabetes, obesity, hepatitis C, and alcoholism.